VUV frequency combs from below-threshold harmonics

Recent demonstrations of high-harmonic generation (HHG) at very high repetition frequencies (~100 MHz) may allow for the revolutionary transfer of frequency combs to the vacuum ultraviolet (VUV). This advance necessitates unifying optical frequency comb technology with strong-field atomic physics. While strong-field studies of HHG have often focused on above-threshold harmonic generation (photon energy above the ionization potential), for VUV frequency combs an understanding of below-threshold harmonic orders and their generation process is crucial. Here we present a new and quantitative study of the harmonics 7-13 generated below and near the ionization threshold in xenon gas. We show multiple generation pathways for these harmonics that are manifested as on-axis interference in the harmonic yield. This discovery provides a new understanding of the strong-field, below-threshold dynamics under the influence of an atomic potential and allows us to quantitatively assess the achievable coherence of a VUV frequency comb generated through below threshold harmonics. We find that under reasonable experimental conditions temporal coherence is maintained. As evidence we present the first explicit VUV frequency comb structure beyond the 3rd harmonic.Comment: 16 pages, 4 figures, 1 tabl

Left Hemisphere Specialization for Oro-Facial Movements of Learned Vocal Signals by Captive Chimpanzees

The left hemisphere of the human brain is dominant in the production of speech and signed language. Whether similar lateralization of function for communicative signal production is present in other primates remains a topic of considerable debate. In the current study, we examined whether oro-facial movements associated with the production of learned attention-getting sounds are differentially lateralized compared to facial expressions associated with the production of species-typical emotional vocalizations in chimpanzees.Still images captured from digital video were used to quantify oro-facial asymmetries in the production of two attention-getting sounds and two species-typical vocalizations in a sample of captive chimpanzees. Comparisons of mouth asymmetries during production of these sounds revealed significant rightward biased asymmetries for the attention-getting sounds and significant leftward biased asymmetries for the species-typical sounds.These results suggest that the motor control of oro-facial movements associated with the production of learned sounds is lateralized to the left hemisphere in chimpanzees. Furthermore, the findings suggest that the antecedents for lateralization of human speech may have been present in the common ancestor of chimpanzees and humans approximately 5 mya and are not unique to the human lineage

Circulating FGF21 Levels Are Progressively Increased from the Early to End Stages of Chronic Kidney Diseases and Are Associated with Renal Function in Chinese

Fibroblast growth factor 21 (FGF21) is a hepatic hormone involved in the regulation of lipid and carbohydrate metabolism. This study aims to test the hypothesis that elevated FGF21 concentrations are associated with the change of renal function and the presence of left ventricular hypertrophy (LVH) in the different stages of chronic kidney disease (CKD) progression.0.05).Plasma FGF21 levels are significantly increased with the development of early- to end-stage CKD and are independently associated with renal function and adverse lipid profiles in Chinese population. Understanding whether increased FGF21 is associated with myocardial hypertrophy in CKD requires further study

Second-line chemotherapy for patients with advanced gastric cancer: who may benefit?

No established second-line chemotherapy is available for patients with advanced gastric cancer failing to respond or progressing to first-line chemotherapy. However, 20–40% of these patients commonly receive second-line chemotherapy. We evaluated the influence of clinico-pathologic factors on the survival of 175 advanced gastric cancer patients, who received second-line chemotherapy at three oncology departments. Univariate and multivariate analyses found five factors which were independently associated with poor overall survival: performance status 2 (hazard ratio (HR), 1.79; 95% CI, 1.16–2.77; P=0.008), haemoglobin ⩽11.5 g l−1 (HR, 1.48; 95% CI, 1.06–2.05; P=0.019), CEA level >50 ng ml−1 (HR, 1.86; 95% CI, 1.21–2.88; P=0.004), the presence of greater than or equal to three metastatic sites of disease (HR, 1.72; 95% CI, 1.16–2.53; P=0.006), and time-to-progression under first-line chemotherapy ⩽6 months (HR, 1.97; 95% CI, 1.39–2.80; P<0.0001). A prognostic index was constructed dividing patients into low- (no risk factor), intermediate- (one to two risk factors), or high- (three to five risk factors) risk groups, and median survival times for each group were 12.7 months, 7.1 months, and 3.3 months, respectively (P<0.001). In the absence of data deriving from randomised trials, this analysis suggests that some easily available clinical factors may help to select patients with advanced gastric cancer who could derive more benefit from second-line chemotherapy

DNA Fragmentation Simulation Method (FSM) and Fragment Size Matching Improve aCGH Performance of FFPE Tissues

Whole-genome copy number analysis platforms, such as array comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) arrays, are transformative research discovery tools. In cancer, the identification of genomic aberrations with these approaches has generated important diagnostic and prognostic markers, and critical therapeutic targets. While robust for basic research studies, reliable whole-genome copy number analysis has been unsuccessful in routine clinical practice due to a number of technical limitations. Most important, aCGH results have been suboptimal because of the poor integrity of DNA derived from formalin-fixed paraffin-embedded (FFPE) tissues. Using self-hybridizations of a single DNA sample we observed that aCGH performance is significantly improved by accurate DNA size determination and the matching of test and reference DNA samples so that both possess similar fragment sizes. Based on this observation, we developed a novel DNA fragmentation simulation method (FSM) that allows customized tailoring of the fragment sizes of test and reference samples, thereby lowering array failure rates. To validate our methods, we combined FSM with Universal Linkage System (ULS) labeling to study a cohort of 200 tumor samples using Agilent 1 M feature arrays. Results from FFPE samples were equivalent to results from fresh samples and those available through the glioblastoma Cancer Genome Atlas (TCGA). This study demonstrates that rigorous control of DNA fragment size improves aCGH performance. This methodological advance will permit the routine analysis of FFPE tumor samples for clinical trials and in daily clinical practice

Pneumococcal Capsular Polysaccharide Structure Predicts Serotype Prevalence

There are 91 known capsular serotypes of Streptococcus pneumoniae. The nasopharyngeal carriage prevalence of particular serotypes is relatively stable worldwide, but the host and bacterial factors that maintain these patterns are poorly understood. Given the possibility of serotype replacement following vaccination against seven clinically important serotypes, it is increasingly important to understand these factors. We hypothesized that the biochemical structure of the capsular polysaccharides could influence the degree of encapsulation of different serotypes, their susceptibility to killing by neutrophils, and ultimately their success during nasopharyngeal carriage. We sought to measure biological differences among capsular serotypes that may account for epidemiological patterns. Using an in vitro assay with both isogenic capsule-switch variants and clinical carriage isolates, we found an association between increased carriage prevalence and resistance to non-opsonic neutrophil-mediated killing, and serotypes that were resistant to neutrophil-mediated killing tended to be more heavily encapsulated, as determined by FITC-dextran exclusion. Next, we identified a link between polysaccharide structure and carriage prevalence. Significantly, non-vaccine serotypes that have become common in vaccinated populations tend to be those with fewer carbons per repeat unit and low energy expended per repeat unit, suggesting a novel biological principle to explain patterns of serotype replacement. More prevalent serotypes are more heavily encapsulated and more resistant to neutrophil-mediated killing, and these phenotypes are associated with the structure of the capsular polysaccharide, suggesting a direct relationship between polysaccharide biochemistry and the success of a serotype during nasopharyngeal carriage and potentially providing a method for predicting serotype replacement

Mechanisms of progression of chronic kidney disease

Chronic kidney disease (CKD) occurs in all age groups, including children. Regardless of the underlying cause, CKD is characterized by progressive scarring that ultimately affects all structures of the kidney. The relentless progression of CKD is postulated to result from a self-perpetuating vicious cycle of fibrosis activated after initial injury. We will review possible mechanisms of progressive renal damage, including systemic and glomerular hypertension, various cytokines and growth factors, with special emphasis on the renin–angiotensin–aldosterone system (RAAS), podocyte loss, dyslipidemia and proteinuria. We will also discuss possible specific mechanisms of tubulointerstitial fibrosis that are not dependent on glomerulosclerosis, and possible underlying predispositions for CKD, such as genetic factors and low nephron number

The role of epigenetics in renal ageing

An ability to separate natural ageing processes from processes specific to morbidities is required to understand the heterogeneity of age-related organ dysfunction. Mechanistic insight into how epigenetic factors regulate ageing throughout the life course, linked to a decline in renal function with ageing, is already proving to be of value in the analyses of clinical and epidemiological cohorts. Noncoding RNAs provide epigenetic regulatory circuits within the kidney, which reciprocally interact with DNA methylation processes, histone modification and chromatin. These interactions have been demonstrated to reflect the biological age and function of renal allografts. Epigenetic factors control gene expression and activity in response to environmental perturbations. They also have roles in highly conserved signalling pathways that modulate ageing, including the mTOR and insulin/insulin-like growth factor signalling pathways, and regulation of sirtuin activity. Nutrition, the gut microbiota, inflammation and environmental factors, including psychosocial and lifestyle stresses, provide potential mechanistic links between the epigenetic landscape of ageing and renal dysfunction. Approaches to modify the renal epigenome via nutritional intervention, targeting the methylome or targeting chromatin seem eminently feasible, although caution is merited owing to the potential for intergenerational and transgenerational effects